The present invention provides compounds that are active at metabotropic glutamate receptors and that are useful for treating neurological and psychiatric diseases and disorders.
Recent advances in the elucidation of the neurophysiological roles of metabotropic glutamate receptors have established these receptors as promising drug targets in the therapy of acute and chronic neurological and psychiatric disorders and diseases. However, the major challenge to the realization of this promise has been the development of metabotropic glutamate receptor subtype-selective compounds.
Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS). Glutamate produces its effects on central neurons by binding to and thereby activating cell surface receptors. These receptors have been divided into two major classes, the ionotropic and metabotropic glutamate receptors, based on the structural features of the receptor proteins, the means by which the receptors transduce signals into the cell, and pharmacological profiles.
The metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors that activate a variety of intracellular second messenger systems following the binding of glutamate. Activation of mGluRs in intact mammalian neurons elicits one or more of the following responses: activation of phospholipase C; increases in phosphoinositide (PI) hydrolysis; intracellular calcium release; activation of phospholipase D; activation or inhibition of adenyl cyclase; increases or decreases in the formation of cyclic adenosine monophosphate (cAMP); activation of guanylyl cyclase; increases in the formation of cyclic guanosine monophosphate (cGMP); activation of phospholipase A2; increases in arachidonic acid release; and increases or decreases in the activity of voltage- and ligand-gated ion channels. Schoepp et al., Trends Pharmacol. Sci. 14:13 (1993); Schoepp, Neurochem. Int. 24:439 (1994); Pin et al., Neuropharmacology 34:1 (1995).
Eight distinct mGluR subtypes, termed mGluR1 through mGluR8, have been identified by molecular cloning. See, for example, Nakanishi, Neuron 13:1031 (1994); Pin et al., Neuropharmacology 34:1 (1995); Knopfel et al., J. Med. Chem. 38:1417 (1995). Further receptor diversity occurs via expression of alternatively spliced forms of certain mGluR subtypes. Pin et al., PNAS 89:10331 (1992); Minakami et al., BBRC 199:1136 (1994); Joly et al., J. Neurosci. 15:3970 (1995).
Metabotropic glutamate receptor subtypes may be subdivided into three groups, Group I, Group II, and Group III mGluRs, based on amino acid sequence homology, the second messenger systems utilized by the receptors, and by their pharmacological characteristics. Nakanishi, Neuron 13:1031 (1994); Pin et al., Neuropharmacology 34:1 (1995); Knopfel et al., J. Med. Chem. 38:1417 (1995).
Group I mGluRs comprise mGluR1, mGluR5, and their alternatively spliced variants. The binding of agonists to these receptors results in the activation of phospholipase C and the subsequent mobilization of intracellular calcium. Electrophysiological measurements have been used to demonstrate these effects in, for example, Xenopus oocytes expressing recombinant mGluR1 receptors. See, for example Masu et al., Nature 349:760 (1991); Pin et al., PNAS 89:10331 (1992). Similar results have been achieved with oocytes expressing recombinant mGluR5 receptors. Abe et al., J. Biol. Chem. 267:13361 (1992); Minakami et al., BBRC 199:1136 (1994); Joly et al., J. Neurosci. 15:3970 (1995). Alternatively, agonist activation of recombinant mGluR1 receptors expressed in Chinese hamster ovary (CHO) cells stimulates PI hydrolysis, cAMP formation, and arachidonic acid release as measured by standard biochemical assays. Aramori et al., Neuron 8:757 (1992).
In comparison, activation of mGluR5 receptors expressed in CHO cells stimulates PI hydrolysis and subsequent intracellular calcium transients, but no stimulation of cAMP formation or arachidonic acid release is observed. Abe et al., J. Biol. Chem. 267:13361 (1992). However, activation of mGluR5 receptors expressed in LLC-PK1 cells results in PI hydrolysis and increased cAMP formation. Joly et al., J. Neurosci. 15:3970 (1995). The agonist potency profile for Group I mGluRs is quisqualate greater than glutamate=ibotenate greater than (2S,1xe2x80x2S,2xe2x80x2S)-2-carboxycyclopropyl)glycine (L-CCG-I) greater than (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD). Quisqualate is relatively selective for Group I receptors, as compared to Group II and Group III mGluRs, but it also is a potent activator of ionotropic AMPA receptors. Pin et al., Neuropharmacology 34:1, Knopfel et al., J. Med. Chem. 38:1417 (1995).
The lack of subtype-specific mGluR agonists and antagonists has impeded elucidation of the physiological roles of particular mGluRs, and the mGluR-associated pathophysiological processes that affect the CNS have yet to be defined. However, work with the available non-specific agonists and antagonists has yielded some general insights about the Group I mGluRs as compared to the Group II and Group III mGluRs.
Attempts at elucidating the physiological roles of Group I mGluRs suggest that activation of these receptors elicits neuronal excitation. Various studies have demonstrated that ACPD can produce postsynaptic excitation upon application to neurons in the hippocampus, cerebral cortex, cerebellum, and thalamus, as well as other brain regions. Evidence indicates that this excitation is due to direct activation of postsynaptic mGluRs, but it also has been suggested that activation of presynaptic mGluRs occurs, resulting in increased neurotransmitter release. Baskys, Trends Pharmacol. Sci. 15:92 (1992); Schoepp, Neurochem. Int. 24:439 (1994); Pin et al., Neuropharmacology 34:1(1995).
Pharmacological experiments implicate Group I mGluRs as the mediators of this excitatory mechanism. The effects of ACPD can be reproduced by low concentrations of quisqualate in the presence of iGluR antagonists. Hu et al., Brain Res. 568:339 (1991); Greene et al., Eur. J. Pharmacol. 226:279 (1992). Two phenylglycine compounds known to activate mGluR1, namely (S)-3-hydroxyphenylglycine ((S)-3HPG) and (S)-3,5-dihydroxyphenylglycine ((S)-DHPG), also produce excitation. Watkins et al., Trends Pharmacol. Sci. 15:33 (1994). In addition, the excitation can be blocked by (S)-4-carboxyphenylglycine ((S)-4CPG), (S)-4-carboxy-3-hydroxyphenylglycine ((S)-4C3HPG), and (+)-alpha-methyl-4-carboxyphenylglycine ((+)-MCPG), compounds known to be mGluR1 antagonists. Eaton et al., Eur. J. Pharmacol. 244:195 (1993); Watkins et al., Trends Pharmacol. Sci. 15:333 (1994).
Metabotropic glutamate receptors have been implicated in a number of normal processes in the mammalian CNS. Activation of mGluRs has been shown to be required for induction of hippocampal long-term potentiation and cerebellar long-term depression. Bashir et al., Nature 363:347 (1993); Bortolotto et al., Nature 368:740 (1994); Aiba et al., Cell 79:365 (1994); Aiba et al., Cell 79:377 (1994). A role for mGluR activation in nociception and analgesia also has been demonstrated. Meller et al., Neuroreport 4: 879 (1993). In addition, mGluR activation has been suggested to play a modulatory role in a variety of other normal processes including synaptic transmission, neuronal development, apoptotic neuronal death, synaptic plasticity, spatial learning, olfactory memory, central control of cardiac activity, waking, motor control, and control of the vestibulo-ocular reflex. For reviews, see Nakanishi, Neuron 13: 1031 (1994); Pin et al., Neuropharmacology 34:1; Knopfel et al., J. Med. Chem. 38:1417 (1995).
Metabotropic glutamate receptors also have been suggested to play roles in a variety of pathophysiological processes and disease states affecting the CNS. These include stroke, head trauma, anoxic and ischemic injuries, hypoglycemia, epilepsy, and neurodegenerative diseases such as Alzheimer""s disease. Schoepp et al., Trends Pharmacol. Sci. 14:13 (1993); Cunningham et al., Life Sci. 54:135 (1994); Hollman et al., Ann. Rev. Neurosci. 17:31 (1994); Pin et al., Neuropharmacology 34:1 (1995); Knopfel et al., J. Med. Chem. 38:1417 (1995). Much of the pathology in these conditions is thought to be due to excessive glutamate-induced excitation of CNS neurons. Because Group I mGluRs appear to increase glutamate-mediated neuronal excitation via postsynaptic mechanisms and enhanced presynaptic glutamate release, their activation probably contributes to the pathology. Accordingly, selective antagonists of Group I mGluR receptors could be therapeutically beneficial, specifically as neuroprotective agents or anticonvulsants.
Preliminary studies assessing therapeutic potentials with the available mGluR agonists and antagonists have yielded seemingly contradictory results. For example, it has been reported that application of ACPD onto hippocampal neurons leads to seizures and neuronal damage (Sacaan et al., Neurosci. Lett. 139:77 (1992); Lipparti et al., Life Sci. 52:85 (1993). Other studies indicate, however, that ACPD inhibits epileptiform activity, and also can exhibit neuroprotective properties. Taschenberger et al., Neuroreport 3:629 (1992); Sheardown, Neuroreport 3:916 (1992); Koh et al., Proc. Natl. Acad. Sci. USA 88:9431 (1991); Chiamulera et al., Eur. J. Pharmacol. 216:335 (1992); Siliprandi et al., Eur. J. Pharmacol. 219:173 (1992); Pizzi et al., J. Neurochem. 61:683 (1993).
It is likely that these conflicting results are due to the lack of selectivity of ACPD, which causes activation of several different mGluR subtypes. In the studies finding neuronal damage it appears that Group I mGluRs were activated, thereby enhancing undesirable excitatory neurotransmission. In the studies showing neuroprotective effects it appears that activation of Group II and/or Group III mGluRs occurred, inhibiting presynaptic glutamate release, and diminishing excitatory neurotransmission.
This interpretation is consistent with the observation that (S)-4C3HPG, a Group I mGluR antagonist and Group II mGluR agonist, protects against audiogenic seizures in DBA/2 mice, while the Group II mGluR selective agonists DCG-IV and L-CCG-I protect neurons from NMDA- and KA-induced toxicity. Thomsen et al., J. Neurochem. 62:2492 (1994); Bruno et al., Eur. J. Pharmacol. 256:109 (1994); Pizzi et al., J. Neurochem. 61:683 (1993).
Based on the foregoing, it is clear that currently available mGluR agonists and antagonists have limited value, due to their lack of potency and selectivity. In addition, most currently available compounds are amino acids or amino acid derivatives that have limited bioavailabilities, thereby hampering in vivo studies to assess mGluR physiology, pharmacology and their therapeutic potential. Compounds that selectively inhibit activation of metabotropic glutamate receptor Group I subtypes should be useful for treatment of neurological disorders and diseases such as senile dementia, Parkinson""s disease, Alzheimer""s disease, Huntington""s Chorea, pain, epilepsy, head trauma, anoxic and ischemic injuries, psychiatric disorders such as schizophrenia, depression, and anxiety, ophthalmological disorders such as various retinopathies, for example, diabetic retinopathies, glaucoma, and neurological disorders of a auditory nature such as tinnitus, and neuropathic pain disorders, including neuropathic diseases states such as diabetic neuropathies, chemotherapy induced neuropathies, post-herpetic neuralgia, and trigeminal neuralgia.
It is apparent, therefore, that identification of potent mGluR agonists and antagonists with high selectivity for individual mGluR subtypes, particularly for Group I receptor subtypes, are greatly to be desired.
It is an object of the present invention, therefore, to identify metabotopic glutamate receptor-active compounds which exhibit a high degree of potency and selectivity for individual metabotropic glutamate receptor subtypes, and to provide methods of making these compounds.
It is a further object of this invention to provide pharmaceutical compositions containing compounds which exhibit a high degree of potency and selectivity for individual metabotropic glutamate receptor subtypes, and to provide methods of making these pharmaceutical compositions.
It is yet another object of this invention to provide methods of inhibiting activation of an mGluR Group I receptor, and of inhibiting neuronal damage caused by excitatory activation of an mGluR Group I receptor.
It is still another object of the invention to provide methods of treating a disease associated with glutamate-induced neuronal damage.
To accomplish these and other objectives, the present invention provides potent antagonists of Group I metabotropic glutamate receptors. These antagonists may be represented by the formula I,
R"Brketopenst"Linker"Brketclosest"Ar
wherein R is an optionally substituted straight or branched chain alkyl, arylalkyl, cycloalkyl, or alkylcycloalkyl group containing 5-12 carbon atoms. Ar is an optionally substituted aromatic, heteroaromatic, arylalkyl, or heteroaralkyl moiety containing up to 10 carbon atoms and up to 4 heteroatoms, and [linker] is xe2x80x94(CH2)nxe2x80x94, where n is 2-6, and wherein up to 4 CH2 groups may independently be substituted with groups selected from the group consisting of C1-C3 alkyl, CHOH, CO, O, S, SO, SO2, N, NH, and NO. Two heteroatoms in the [linker] may not be adjacent except when those atoms are both N (as in xe2x80x94Nxe2x95x90Nxe2x80x94 of xe2x80x94NHxe2x80x94NHxe2x80x94) or are N and S as in a sulfonamide. Two adjacent CH2 groups in [linker] also may be replaced by a substituted or unsubstituted alkene or alkyne group. Pharmaceutically acceptable salts of the compounds also are provided.
In one embodiment of the invention, Ar comprises a ring system selected from the group consisting of benzene, thiazole, furyl, pyranyl, 2H-pyrrolyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl benzothiazole, benzimidazole, 3H-indolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalizinyl, naphthyridinyl, quinazolinyl, cinnolinyl, isothiazolyl, quinoxalinyl indolizinyl, isoindolyl, benzothienyl, benzofuranyl, isobenzofuranyl, and chromenyl rings. Ar optionally may independently be substituted with up to two C1-C3 alkyl groups, or up to two halogen atoms, where halogen is selected from F, Cl, Br, and I.
In another embodiment of the invention, R contains 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms, where some or all of the hydrogen atoms on two carbon atoms optionally may be replaced with substituents independently selected from the group consisting of F, Cl, OH, OMe, xe2x95x90O, and xe2x80x94COOH.
In yet another embodiment [linker] comprises an amide, ester, or thioester group.
In a preferred embodiment, R comprises a moiety selected from the group consisting of substituted or unsubstituted adamantyl, 2-adamantyl, (1S,2S,3S,5R)-isopinocamphenyl, tricyclo[4.3.1.1(3,8)]undec-3-yl, (1S,2R,5S)-cis-myrtanyl, (1R,2R,4S)-isobornyl, (1R,2R,3R,5S)-isopinocamphenyl, (1S,2S,5S)-trans-myrtanyl, (1R,2R,5R)-trans-myrtanyl, (1R,2S,4S)-bornyl, 1-adamantanemethyl, 3-noradamantyl, (1S,2S,3S,5R)-3-pinanemethyl, cyclooctyl, xcex1,xcex1-dimethylphenethyl, (S)-2-phenyl-1-propyl, cycloheptyl, 4-methyl-2-hexyl groups, 2,2,3,3,4,4,4-heptafluorobutyl, 4-ketoadamantyl, 3-phenyl-2-methylpropyl, 3,5-dimethyladamantyl, trans-2-phenylcyclopropyl, 2-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 2-(o-methoxyphenyl)ethyl, 2-(1,2,3,4-tetrahydronaphthyl), 4-phenylbutyl, 2-methyl-2-phenylbutyl, 2-(m-fluorophenyl)ethyl, 2-(p-fluorophenyl)ethyl, 2-(3-hydroxy-3-phenyl)propyl, (S)-2-hydroxy-2-phenylethyl, (R)-2-hydroxy-2-phenylethyl, 2-(3-m-chlorophenyl-2-methyl)propyl, 2-(3-p-chlorophenyl-2-methyl)propyl, 4-tert-butyl-cyclohexyl, (S)-1-(cyclohexyl)ethyl, 2-(3-(3,4-dimethylphenyl)-2-methyl)propyl, 3,3-dimethylbutyl, 2-(5-methyl)hexyl, 1-myrtanyl, 2-bornyl, 3-pinanemethyl, 2,2,3,3,4,4,5,5-octafluoropentyl, p-fluoro-xcex1,xcex1-dimethylphenethyl, 2-naphthyl, 2-bornanyl, cyclohexylmethyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 3,4-dimethylcyclohexyl, 5-chloro-tricyclo[2.2.1]heptyl, o-xcex1,xcex1-dimethylphenethyl, 2-indanyl, 2-spiro[4.5]decyl, 2-phenylethyl, 1-adamantylethyl, 1-(1-bicyclo[2.2.1]hept-2-yl)ethyl, 2-(2-methyl-2-phenylpropyl), 2-(o-fluorophenyl)ethyl, 1-(cyclohexyl)ethyl, and cyclohexyl.
In a still further embodiment of the invention, Ar comprises a group having the formula 
where X1, X2, X3, and X4 independently can be N or CH, provided that not more than two of X1, X2, X3, and X4 can be N. In a preferred embodiment, X1 is N, and/or X2 is N. In another embodiment, X3 is N. In still another embodiment, X1 is CH and X2 is N.
In yet another embodiment, Ar is an optionally substituted 2-, 3-, or 4-pyridyl moiety, or Ar is a 6-benzothiazolyl moiety. The compound is selected from the group consisting of N-[6-(2-Methylquinolyl)]-1-adamantanecarboxamide, N-(6-Quinolyl)-1-adamantanecarboxamide, N-(2-Quinolyl)-1-adamantanecarboxamide, N-(3-Quinolyl)-1-adamantane-carboxamide, 6-Quinolyl-1-adamantanecarboxylate, 1-Adamantyl-6-quinolinecarboxylate, 2,2,3,3,4,4,5,5-Octafluoro-1-pentyl-6-quinolinecarboxylate, 1-Adamantanemethyl-6-quinolinecarboxylate, 1-Adamantyl-2-quinoxalinecarboxylate, N-(1-Adamantyl)-3-quinoline-carboxamide, N-(1-Adamantyl)-2-quinolinecarboxamide, N-(2-Adamantyl)-2-quinoxalinecarboxamide, N-[(1R,2R,3R,5S)-3-Pinanemethyl]-2-quinoxaline-carboxamide, N-(1-Adamantyl)-2-quinoxalinecarboxamide, N-(1-Adamantyl)-6-quinolinecarboxamide, N-(exo-2-Norbornanyl)-2-quinoxalinecarboxamide, N-[(1R,2S,4S)-Bornyl]-2-quinoxalinecarboxamide, N-(3-Noradamantyl)-2-quinoxalinecarboxamide, N-[(1R,2R,3R,5S)Iso-pinocamphenyl]-2-quinoxalinecarboxamide, N-[(1S,2S,3S,5R)-Isopinocamphenyl]-2-quinoxaline-carboxamide, N-(5-Chloro-[2.2.1.0]tricyclo-2,6-hepta-3-yl)-2-quinoxalinecarboxamide, N-([4.3.1.1)Tricyclo-3,8-undeca-3-yl)-2-quinoxalinecarboxamide, N-[(1S,2R,5S)-cis-Myrtanyl]-2-quinoxalinecarboxamide, N-[(1R,2R,4S)Isobornyl]-2-quinoxalinecarboxamide, N-[endo-(xc2x1)-2-Norbornanyl]-2-quinoxalinecarboxamide, N-[(R)-2-Phenyl-1propyl]-2-quinoxalinecarboxamide, N-[(S)-2-Phenyl-1-propyl]-2-quinoxalinecarboxamide, N-(2-Indanyl)-2-quinoxalinecarboxamide, 1-Adamantanemethyl 6-quinolyl ether, 1-Adamantyl-3-quinolinecarboxylate, N-(xcex1,xcex1-Dimethylphenethyl)-2-quinoxalinecarboxamide, N-(xcex1,xcex1-Dimethyl-2-chlorophenethyl)-2-quinoxalinecarboxamide, N-(xcex1,xcex1-Dimethyl-4-fluorophenethyl)-2-quinoxalinecarboxamide, N-(xcex2-Methylphenethyl)-2-quinoxalinecarboxamide, N-(3-Methylcyclohexyl)-2-quinoxalinecarboxamide, N-(2,3-Dimethylcyclohexyl)-2-quinoxalinecarboxamide, N-[(1S,2S,3S,5R)-3-Pinanemethyl]-2-quinoxaline-carboxamide, N-(1-Adamantanemethyl)-2-quinoxaline-carboxamide, N-(4-Methylcyclohexyl)-2-quinoxaline-carboxamide, N-[(1S,2S,5S)-trans-Myrtanyl]-2-quinoxaline-carboxamide, and N-[(1R,2R,5R)-trans-Myrtanyl]-2-quinoxalinecarboxamide, and pharmaceutically acceptable salts thereof.
In a preferred embodiment, the compound is selected from the group consisting of N-(1-Adamantyl)-3-quinolinecarboxamide, N-(1-Adamantyl)-2-quinolinecarboxamide, N-(2-Adamantyl)-2-quinoxaline-carboxamide, N-[(1R,2R,3R,5S)-3-Pinanemethyl]-2-quinoxaline-carboxamide, N-(1-Adamantyl)-2-quinoxaline-carboxamide, N-(1-Adamantyl)-6-quinolinecarboxamide, N-(exo-2-Norbornanyl)-2-quinoxaline-carboxamide, N-[(1R,2S,4S)-Bornyl]-2-quinoxaline-carboxamide, N-(3-Noradamantyl)-2-quinoxaline-carboxamide, N-[(1R,2R,3R,5S)-Isopinocamphenyl]-2-quinoxaline-carboxamide, N-[(1S,2S,3S,5R)-Isopinocamphenyl]-2-quinoxaline-carboxamide, N-(5-Chloro-[2.2.1.0]tricyclo-2,6-hepta-3-yl)-2-quinoxaline-carboxamide, N-([4.3.1.1]Tricyclo-3,8-undeca-3-yl)-2-quinoxaline-carboxamide, N-[(1S,2R,5S)-cis-Myrtanyl]-2-quinoxaline-carboxamide, N-[(1R,2R,4S)Isobornyl)-2-quinoxaline-carboxamide, N-[endo-(xc2x1)-2-Norbornanyl]-2-quinoxaline-carboxamide, N-[(1S,2S,3S,5R)-3-Pinanemethyl]-2-quinoxalinecarboxamide, N-(1-Adamantanemethyl)-2-quinoxalinecarboxamide, N-[(1S,2S,5S)-trans-Myrtanyl]-2-quinoxalinecarboxamide, and N-[(1R,2R,5R)-trans-Myrtanyl]-2-quinoxalinecarboxamide, and pharmaceutically acceptable salts thereof.
In another embodiment, the compound is selected from the group consisting of N-[6-(2-Methylquinolyl)]-1-adamantanecarboxamide, N-(6-Quinolyl)-1-adamantane-carboxamide, N-(2-Quinolyl)-1-adamantanecarboxamide, and N-(3-Quinolyl)-1-adamantanecarboxamide, N-(3-Methylcyclohexyl)-2-quinoxalinecarboxamide, N-(2,3-Dimethylcyclohexyl)-2-quinoxalinecarboxamide, N-[(1S,2S,3S,5R)-3-Pinanemethyl]-2-quinoxalinecarboxamide, N-(1-Adamantanemethyl)-2-quinoxalinecarboxamide, and N-(4-Methylcyclohexyl)-2-quinoxalinecarboxamide, N-[(R)-2-Phenyl-1-propyl-2-quinoxalinecarboxamide, N-[(S)-2-Phenyl-1-propyl]-2-quinoxalinecarboxamide, N-(2-Indanyl)-2-quinoxalinecarboxamide, N-(xcex1-xcex1-Dimethylphenethyl)-2-quinoxalinecarboxamide, N-(xcex1,xcex1-Dimethyl-2-chlorophenethyl)-2-quinoxalinecarboxamide, N-(xcex1,xcex1-Dimethyl-4-fluorophenethyl)-2-quinoxaline-carboxamide, and N-(xcex2-Methylphenethyl)-2-quinoxaline-carboxamide, 1-Adamantanemethyl 6-quinolyl ether, 6-Quinolyl-1-adamantanecarboxylate, 1-Adamantyl-6-quinolinecarboxylate, 2,2,3,3,4,4,5,5-Octafluoro-1-pentyl 6-quinolinecarboxylate, 1-Adamantanemethyl 6-quinolinecarboxylate, 1-Adamantyl-2-quinoxalinecarboxylate, and 1-Adamantyl-3-quinolinecarboxylate, and pharmaceutically acceptable salts thereof.
In yet another embodiment, the compound is selected from the group consisting of 3-(1-Adamantanemethoxy)-2-chloroquinoxaline, 2-(1-Adamantanemethoxy)-3-methylquinoxaline, 3-(1-Adamantanemethoxy)-2-fluoroquinoxaline, 2-(1-Adamantanemethoxy)-3-trifluoromethylquinoxaline, N-[2-(4-Phenylthiazolyl)]-1-adamantanecarboxamide, N-[2-(5-Methyl-4-phenylthiazolyl)]-1-adamantanecarboxamide, 1-(1-Adamantyl)-2-(benzothiazol-2-ylsulfanyl)ethanone, N-(1-Adamantyl)-2-chloroquinoxaline-3-carboxamide, N-(1-Adamantyl)-3-methylquinoxaline-2-carboxamide, and N-(1-Adamantyl)-1-oxyquinoxaline-3-carboxamide, 4-Chlorophenyl 3-coumarincarboxylate, 2-(1-Adamantanemethylsulfanyl)quinoxaline, 3-(1-Adamantanemethoxy)-2-chloropyrazine, 1-(1-Adamantyl)-2-(4,6-dimethylpyrimidin-2-ylsulfanyl)ethanone, 1-(1-Adamantyl)-2-(2-anisylsulfanyl)ethanone, 3-(1-Adamantanemethoxy)-1H-quinoxalin-2-one, 1-(1-Adamantyl)-2-(3-anisylsulfanyl)ethanone, 1-(1-Adamantyl)-2-(4-anisylsulfanyl)ethanone, 1-(1-Adamantyl)-2-(4-chlorophenylsulfanyl)ethanone, 1-(1-Adamantyl)-2-(2-naphthylsulfanyl)ethanone, N-(2-[6-(1-Piperidinyl)pyrazinyl])-1-adamantanecarboxamide, N-(2-[6-(1-Piperidinyl)pyrazinyl])adamantan-1-ylmethylcarboxamide, 1-(1-Adamantyl)-2-(1-naphthylsulfanyl)ethanone, 1-(1-Adamantyl)-2-(8-quinolylsulfanyl)ethanone hydrochloride, 1-(1-Adamantyl)-2-(4-trifluoromethoxyphenoxy)ethanone, 2-(1-Adamantanemethoxy)quinoxaline, N-(trans-4-Methylcyclohexyl)-2-quinoxalinecarboxamide, N-(cis-4-Methylcyclohexyl)-2-quinoxalinecarboxamide, N-(trans-4-Methylcyclohexyl)-2-quinolinecarboxamide, N-(trans-4-Methylcyclohexyl)-3-quinolinecarboxamide, and N-(trans-4-Methylcyclohexyl)-6-quinolinecarboxamide, 2-(1-Adamantanemethylsulfinyl)-benzothiazole, N-(4-Phenylbutyl)-2-quinoxalinecarboxamide, 1-(1-Adamantyl)-2-(4,6-dimethylpyrimidin-2-ylsulfanyl)ethanol, 1-(1-Adamantyl)-2-(3-chloroquinoxal-2-yl)ethanone, 2-(1-Adamantanemethylsulfanyl)-3-methylquinoxaline, N-(1-Adamantyl)-2-anisamide, N-(1-Adamantanemethyl)-2-anisamide, 1-(1-Adamantyl)-2-(4-chlorophenylsulfanyl)ethanone, 2-(1-Adamantanemethylsulfonyl)-3-methylquinoxaline, 1-(1-Adamantyl)-2-(4-fluorophenylsulfanyl)ethanone, 1-(1-Adamantyl)-2-(3-fluorophenylsulfanyl)ethanone, 1-(1-Adamantyl)-2-(2-methoxyphenoxy)ethanone, 1-(4-Anisylsulfanyl)butan-2-one, 1-(1-Adamantyl)-2-(4-anisidinyl)ethanone hydrochloride, 3,3-Dimethyl-1-(4-anisylsulfanyl)butan-2-one, 1-(4-Biphenyl)-2-(4-anisylsulfanyl)ethanone, 1-(1-Adamantyl)-2-(2-trifluoromethoxyphenylsulfanyl)ethanone, 1-(1-Adamantyl)-2-(3-methylquinoxal-2-ylsulfanyl)ethanone, 1-(1-Adamantyl)-2-(2-anisidinyl)ethanone hydrochloride, 1-(1-Adamantyl)-2-(4-trifluoromethoxyphenylamino)ethanone hydrochloride, 1-(1-Adamantyl)-2-(N-methyl-4-anisidinyl)ethanone hydrochloride, N-(1-Adamantyl)-7-trifluoromethylquinoline-3-carboxamide, N-(1-Adamantyl)-2-(1-piperizinyl)quinoxaline-3-carboxamide, N-(1-Adamantyl)-2-(2-aminoethylamino)quinoxaline-3-carboxamide, Methyl N-(3-quinolyl)-3-carboxyadamantane-1-carboxamide, 1-(1-Adamantyl)-2-[(R)-1-(1-naphthyl)ethan-1-ylamino]ethanone, N-(1-Adamantyl)-2-methoxyquinoxaline-3-carboxamide, Ethyl N-(1-adamantyl)-2-(3-propanoylamino)quinoxaline-3-carboxamide, N-(4-Chlorophenyl)-2,3-dimethylquinoxaline-6-carboxamide, N-(1-Adamantyl)-6,7-dimethylquinoxaline-2-carboxamide, N-((S)-1-Tetralinyl)-2-quinoxalinecarboxamide, N-(4-Chlorophenethyl)-2-quinoxalinecarboxamide, N-(6-Quinolyl)-2-quinoxalinecarboxamide, N-(1-Tetralinmethyl)-2-quinoxalinecarboxamide, N-(1-Indanmethyl)-2-quinoxalinecarboxamide, N-(4,4-Dimethylcyclohexyl)-2-quinoxalinecarboxamide, and pharmaceutically acceptable salts thereof.
In yet other embodiments, the compound is selected from the group consisting of N-[2-(2-fluorophenyl)propyl]quinoxaline-2-carboxamide, N-(pentyl)quinoxaline-2-carboxamide, N-(trans-4-phenylcyclohexyl)quinoxaline-2-carboxamide, N-(trans-4-methylcyclohexyl)indole-5-carboxamide, N-(6-quinolinyl)-4-methylcyclohexane-1-carboxamide, N-(1-methyl-4-phenylcyclohexyl)quinoxaline-2-carboxamide, N-(trans-4-methylcyclohexyl)benzothiaphene-2-carboxamide, N-(trans-4-methylcyclohexyl)benzofuran-2-carboxamide, N-(3-quinolinyl)quinoxaline-2-carboxamide hydrochloride, N-(trans-4-methylcyclohexyl)-6-bromopicolinamide, N-(adamantyl)-5-(1-piperidine)nicotinamide, N-(trans-4-methylcyclohexyl)-2-carboxamidebenzothiazole, N-[2-(2,6-difluorophenyl)ethyl]quinoxaline-2-carboxamide, N-(trans-4-methylcyclohexyl)-6-methoxyquinoline-3-carboxamide, N-(trans-4-methylcyclohexyl)-7-methoxyquinoline-3-carboxamide, N-(trans-4-methylcyclohexyl)-5-fluoroquinoline-3-carboxamide, N-(trans-4-methylcyclohexyl)-7-fluoroquinoline-3-carboxamide, N-(trans-4-methylcyclohexyl)-6-fluoroquinoline-3-carboxamide, N-(trans-4-methylcyclohexyl)-8-fluoroquinoline-3-carboxamide, N-(trans-4-methylcyclohexyl)-6,7-methylenedioxyquinoline-3-carboxamide, N-(trans-4-methylcyclohexyl)-6,7-ethylenedioxyquinoline-3-carboxamide, N-(trans-4-methylcyclohexyl)-6,8-difluoroquinoline-3-carboxamide, N-(trans-4-methylcyclohexyl)-6-methoxy-7-fluoroquinoline-3-carboxamide, N-(trans-4-methylcyclohexyl)-7-trifluoromethylquinoline-3-carboxamide, N-(trans-4-methylcyclohexyl)-8-trifluoromethylquinoline-3-carboxamide, N-(trans-4-methylcyclohexyl)-6-fluoroquinoxaline-2-carboxamide, N-(trans-4-methylcyclohexyl)-5-fluoroquinoxaline-2-carboxamide, N-(trans-4-methylcyclohexyl)-6-trifluoromethylquinoxaline-2-carboxamide, N-(trans-4-methylcyclohexyl)-6-methoxyquinoxaline-2-carboxamide, and N-(trans-4-methylcyclohexyl)-6,7-methylenedioxyquinoxaline-2-carboxamide, N-(1-adamantyl)-2-quinoxalinecarboxamide, N-(xcex1,xcex1-dimethylphenethyl)-2-quinoxalinecarboxamide, N-(3-noradamantyl)-2-quinoxalinecarboxamide, N-[(1S,2R,5S)-cis-myrtanyl]-2-quinoxalinecarboxamide, (1-adamantylmethyl)-2-(3-chloro)quinoxalylether, (1-adamantylmethyl)-2-(3-methyl)quinoxalylether, N-(6-quinolinyl)quinoxaline-2-carboxamide, N-(trans-4-methylcyclohexyl)-2-quinoxalinecarboxamide, N-(4,4-dimethylcyclohexyl)quinoxaline-2-carboxamide, N-(trans-4-methylcyclohexyl)quinoline-2-carboxamide, N-(trans-4-methylcyclohexyl)quinoline-3-carboxamide, and N-(trans-4-methylcyclohexyl)quinoline-6-carboxamide, and pharmaceutically acceptable salts thereof.
In another embodiment, the compound has the structure 
Where X1 and X2 independently are CH or N, X3 is N or Cxe2x80x94E, A, B, D, and E independently are selected from the group consisting of H, OMe, F, and CF3, (preferably at least two of A, B, D, and E are H), or B and D together are xe2x80x94Oxe2x80x94(CH2)xe2x80x94Oxe2x80x94 or Oxe2x80x94(CH2)2xe2x80x94Oxe2x80x94, R is selected from the group consisting of C4-C6 alkyl, 
where K is H or Me, G1 is H, Me, or phenyl, G2, K, L, and M independently are H or Me, n is 0, 1 or 2, and X4 and X5 independently are N or CH.
In accordance with another embodiment of the invention, there has been provided a pharmaceutical composition comprising a compound as set forth above, together with a pharmaceutically acceptable diluent or excipient.
In accordance with still another embodiment of the invention, there has been provided a method of making a compound as set forth above, comprising reacting a compound containing an activated carboxylic acid group with a compound containing an amine, hydroxyl, or thiol group.
In accordance with a still further embodiment of the invention, there has been provided a method of inhibiting activation of an mGluR Group I receptor, comprising treating a cell containing said mGluR Group I receptor with an effective amount of a compound as set forth above.
In yet another embodiment of the invention, there has been provided a method of inhibiting neuronal damage caused by excitatory activation of an mGluR Group I receptor, comprising treating neurons with an effective amount of a compound as set forth above.
In accordance with a further embodiment of the invention, there has been provided a method of treating a disease associated with glutamate-induced neuronal damage, comprising administering to a patient suffering from said disease an effective amount of a composition as set forth above.
Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.